DESCRIPTION (Investigator's abstract): Type 2 diabetes among youth, particularly in children of African descent, is an emerging public health problem for which there is a great potential to improve primary and secondary prevention. Increasing evidence indicates that type 2 diabetes is a complex genetic disorder in which defects in insulin action and insulin secretion contribute to the phenotype expression of the disease. In this application we propose a series of genetic and clinical studies to elucidate the genetic basis of maturity-onset diabetes of the young (MODY) in families of African descent. In contrast to a multitude of studies on the genetic etiology of MODY in Caucasian and Asian pedigrees, no family-based studies have been carried out in pedigrees of African descent. In studies initiated in 1996, pedigrees with early-onset type 2 diabetes and autosomal-dominant inheritance were ascertained from Jamaica and the U.S., and DNA was isolated from a total of eight families, two of which are large enough to independently establish linkage. In this application we propose to apply modern methods in human genetics and clinical investigation to characterize the physiologic defect and identify the MODY gene(s) in these pedigrees. The identification of genes that cause early-onset type 2 diabetes in people of African descent is expected to have a major impact on our understanding of its pathogenesis and possibly of the more common polygenic forms of type 2 diabetes. Furthermore, the identification of the causal genes will likely reveal new physiological pathways and may lead to identification of new drug targets and, ultimately, the development of new, less empirical therapies.